Advertisement

Endothelin-1 increases expression and activity of arginase 2 via ETB receptors and is co-expressed with arginase 2 in human atherosclerotic plaques

  • Author Footnotes
    1 These authors contributed equally to this work.
    ,
    Author Footnotes
    2 Present address: Department of Cardiology, Landspitali Haskolasjukrahus, Reykjavik, Iceland.
    Arnar Rafnsson
    Correspondence
    Corresponding author.
    Footnotes
    1 These authors contributed equally to this work.
    2 Present address: Department of Cardiology, Landspitali Haskolasjukrahus, Reykjavik, Iceland.
    Affiliations
    From the Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Ljubica Perisic Matic
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Mariette Lengquist
    Affiliations
    Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Ali Mahdi
    Affiliations
    From the Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Alexey Shemyakin
    Affiliations
    From the Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Gabrielle Paulsson-Berne
    Affiliations
    Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine. Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • Göran K. Hansson
    Affiliations
    Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine. Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • Anders Gabrielsen
    Affiliations
    From the Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine. Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • Ulf Hedin
    Affiliations
    Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Jiangning Yang
    Affiliations
    From the Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • John Pernow
    Affiliations
    From the Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    2 Present address: Department of Cardiology, Landspitali Haskolasjukrahus, Reykjavik, Iceland.

      Highlights

      • ET-1 and its receptors ETA and ETB were highly expressed in endothelial cells, vascular smooth muscle cells and macrophages.
      • ET-1 and arginase were localized in the necrotic core and closely associated.
      • The expression of ET-1 and ETB receptors was increased in carotid plaques from symptomatic patients.
      • ET-1 increased arginase expression and activity in endothelial cells and arginase activity in THP-1-derived macrophages.
      • ET-1 stimulated reactive oxygen species formation in THP-1-derived macrophages via an arginase-dependent mechanism.

      Abstract

      Background and aims

      Endothelin-1 (ET-1) and arginase are both suggested to be involved in the inflammatory processes and development of endothelial dysfunction in atherosclerosis. However, information regarding the roles of ET-1 and arginase, as well as the interactions between the two in human atherosclerosis, is scarce. We investigated the expression of ET-1 and its receptors, ETA and ETB, as well as arginase in human carotid atherosclerotic plaques and determined the functional interactions between ET-1 and arginase in endothelial cells and THP-1-derived macrophages.

      Methods

      Carotid plaques and blood samples were retreived from patients undergoing surgery for symptomatic or asymptomatic carotid stenosis. Plaque gene and protein expression was determined and related to clinical characteristics. Functional interactions between ET-1 and arginase were investigated in endothelial cells and THP-1 cells.

      Results

      Expression of ET-1 and ETB receptors was increased in plaques from patients with symptomatic carotid artery disease. ET-1 was co-localized with arginase 1 and arginase 2 in the necrotic core, together with macrophage markers CD163 and CD68. Arginase 2, ET-1 and ETB receptors were expressed in endothelial cells as well as in smooth muscle cells in the fibrous cap. ET-1 increased arginase 2 mRNA expression and arginase activity in endothelial cells and arginase activity in macrophages. Moreover, ET-1 stimulated formation of reactive oxygen species (ROS) in THP-1-derived macrophages via an arginase-dependent mechanism.

      Conclusions

      This is the first study that demonstrates co-localization of ET-1 and arginase 2 in human atherosclerotic plaques. ET-1 stimulated arginase 2 expression and activity in endothelial cells, as well as arginase activity and ROS formation in macrophages via an arginase-dependent mechanism. These results indicate an important interaction between the ET pathway and arginase in human atherosclerotic plaques.

      Graphical abstract

      Keywords

      Abbreviations:

      ET-1 (Endothelin-1), ETA (endothelin receptor A), ETB (endothelin receptor B), Arg (Arginase), NO (nitric oxide), HCAECs (Human carotid artery endothelial cells)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Barquera S.
        • Pedroza-Tobias A.
        • Medina C.
        • Hernandez-Barrera L.
        • Bibbins-Domingo K.
        • Lozano R.
        • Moran A.E.
        Global overview of the epidemiology of atherosclerotic cardiovascular disease.
        Arch. Med. Res. 2015; 46: 328-338
        • Lerman A.
        • Zeiher A.M.
        Endothelial function: cardiac events.
        Circulation. 2005; 111: 363-368
        • Widlansky M.E.
        • Gokce N.
        • Keaney Jr., J.F.
        • Vita J.A.
        The clinical implications of endothelial dysfunction.
        J. Am. Coll. Cardiol. 2003; 42: 1149-1160
        • Park K.H.
        • Park W.J.
        Endothelial dysfunction: clinical implications in cardiovascular disease and therapeutic approaches.
        J. Korean Med. Sci. 2015; 30: 1213-1225
        • Pernow J.
        • Shemyakin A.
        • Bohm F.
        New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus.
        Life Sci. 2012; 91: 507-516
        • Lerman A.
        • Webster M.W.
        • Chesebro J.H.
        • Edwards W.D.
        • Wei C.M.
        • Fuster V.
        • Burnett Jr., J.C.
        Circulating and tissue endothelin immunoreactivity in hypercholesterolemic pigs.
        Circulation. 1993; 88: 2923-2928
        • Zeiher A.M.
        • Ihling C.
        • Pistorius K.
        • Schachinger V.
        • Schaefer H.E.
        Increased tissue endothelin immunoreactivity in atherosclerotic lesions associated with acute coronary syndromes.
        Lancet. 1994; 344: 1405-1406
        • Barton M.
        • Haudenschild C.C.
        • d'Uscio L.V.
        • Shaw S.
        • Munter K.
        • Luscher T.F.
        Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice.
        Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 14367-14372
        • Dashwood M.R.
        • Tsui J.C.
        Further evidence for a role of endothelin-1 (ET-1) in critical limb ischaemia.
        J Cell Commun. Signal. 2010; 5: 45-49
        • Cerrato R.
        • Cunnington C.
        • Crabtree M.J.
        • Antoniades C.
        • Pernow J.
        • Channon K.M.
        • Bohm F.
        Endothelin-1 increases superoxide production in human coronary artery bypass grafts.
        Life Sci. 2012; 91: 723-728
        • Steppan J.
        • Nyhan D.
        • Berkowitz D.E.
        Development of novel arginase inhibitors for therapy of endothelial dysfunction.
        Front. Immunol. 2013; 4: 278
        • Kovamees O.
        • Shemyakin A.
        • Pernow J.
        Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus.
        PLoS One. 2014; 9e103260
        • Shemyakin A.
        • Kovamees O.
        • Rafnsson A.
        • Bohm F.
        • Svenarud P.
        • Settergren M.
        • Jung C.
        • Pernow J.
        Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus.
        Circulation. 2012; 126: 2943-2950
        • Zhou Z.
        • Mahdi A.
        • Tratsiakovich Y.
        • Zahoran S.
        • Kovamees O.
        • Nordin F.
        • Uribe Gonzalez A.E.
        • Alvarsson M.
        • Ostenson C.G.
        • Andersson D.C.
        • Hedin U.
        • Hermesz E.
        • Lundberg J.O.
        • Yang J.
        • Pernow J.
        Erythrocytes from patients with type 2 diabetes induce endothelial dysfunction via arginase I.
        J. Am. Coll. Cardiol. 2018; 72: 769-780
        • Corraliza I.M.
        • Soler G.
        • Eichmann K.
        • Modolell M.
        Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages.
        Biochem. Biophys. Res. Commun. 1995; 206: 667-673
        • Hayashi T.
        • Esaki T.
        • Sumi D.
        • Mukherjee T.
        • Iguchi A.
        • Chaudhuri G.
        Modulating role of estradiol on arginase II expression in hyperlipidemic rabbits as an atheroprotective mechanism.
        Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 10485-10490
        • Ryoo S.
        • Gupta G.
        • Benjo A.
        • et al.
        Endothelial arginase II: a novel target for the treatment of atherosclerosis.
        Circ. Res. 2008; 102: 923-932
        • Ming X.F.
        • Rajapakse A.G.
        • Yepuri G.
        • Xiong Y.
        • Carvas J.M.
        • Ruffieux J.
        • Scerri I.
        • Wu Z.
        • Popp K.
        • Li J.
        • Sartori C.
        • Scherrer U.
        • Kwak B.R.
        • Montani J.P.
        • Yang Z.
        Arginase II promotes macrophage inflammatory responses through mitochondrial reactive oxygen species, contributing to insulin resistance and atherogenesis.
        J Am. Heart Assoc. 2012; 1e000992
        • Rabelo L.A.
        • Ferreira F.O.
        • Nunes-Souza V.
        • da Fonseca L.J.
        • Goulart M.O.
        Arginase as a critical prooxidant mediator in the binomial endothelial dysfunction-atherosclerosis.
        Oxid. Med. Cell Longevity. 2015; 2015: 924860
        • Perisic L.
        • Aldi S.
        • Sun Y.
        • Folkersen L.
        • Razuvaev A.
        • Roy J.
        • Lengquist M.
        • Akesson S.
        • Wheelock C.E.
        • Maegdefessel L.
        • Gabrielsen A.
        • Odeberg J.
        • Hansson G.K.
        • Paulsson-Berne G.
        • Hedin U.
        Gene expression signatures, pathways and networks in carotid atherosclerosis.
        J. Intern. Med. 2016; 279: 293-308
        • Henderson R.D.
        • Eliasziw M.
        • Fox A.J.
        • Rothwell P.M.
        • Barnett H.J.
        Angiographically defined collateral circulation and risk of stroke in patients with severe carotid artery stenosis. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.
        Stroke. 2000; 31: 128-132
        • Halliday A.
        • Mansfield A.
        • Marro J.
        • Peto C.
        • Peto R.
        • Potter J.
        • Thomas D.
        • Group MRCACSTC
        Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial.
        Lancet. 2004; 363: 1491-1502
        • Razuvaev A.
        • Ekstrand J.
        • Folkersen L.
        • Agardh H.
        • Markus D.
        • Swedenborg J.
        • Hansson G.K.
        • Gabrielsen A.
        • Paulsson-Berne G.
        • Roy J.
        • Hedin U.
        Correlations between clinical variables and gene-expression profiles in carotid plaque instability.
        Eur. J. Vasc. Endovasc. Surg. : Off. J. Eur. Soc. Vasc. Surg. 2011; 42: 722-730
        • Folkersen L.
        • Persson J.
        • Ekstrand J.
        • Agardh H.E.
        • Hansson G.K.
        • Gabrielsen A.
        • Hedin U.
        • Paulsson-Berne G.
        Prediction of ischemic events on the basis of transcriptomic and genomic profiling in patients undergoing carotid endarterectomy.
        Mol. Med. 2012; 18: 669-675
        • Perisic L.
        • Hedin E.
        • Razuvaev A.
        • Lengquist M.
        • Osterholm C.
        • Folkersen L.
        • Gillgren P.
        • Paulsson-Berne G.
        • Ponten F.
        • Odeberg J.
        • Hedin U.
        Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2013; 33: 2432-2443
        • Matic L.P.
        • Jesus Iglesias M.
        • Vesterlund M.
        • et al.
        Novel multiomics profiling of human carotid atherosclerotic plaques and plasma reveals biliverdin reductase B as a marker of intraplaque hemorrhage.
        JACC Basic Transl. Sci. 2018; 3: 464-480
        • Soldano S.
        • Paolino S.
        • Pizzorni C.
        • Trombetta A.C.
        • Montagna P.
        • Brizzolara R.
        • Corallo C.
        • Giordano N.
        • Sulli A.
        • Cutolo M.
        Dual endothelin receptor antagonists contrast the effects induced by endothelin-1 on cultured human microvascular endothelial cells.
        Clin. Exp. Rheumatol. 2017; 35: 484-493
        • Yang J.
        • Gonon A.T.
        • Sjoquist P.O.
        • Lundberg J.O.
        • Pernow J.
        Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 15049-15054
        • Yang J.
        • Zheng X.
        • Mahdi A.
        • Zhou Z.
        • Tratsiakovich Y.
        • Jiao T.
        • Kiss A.
        • Kovamees O.
        • Alvarsson M.
        • Catrina S.B.
        • Lundberg J.O.
        • Brismar K.
        • Pernow J.
        Red blood cells in type 2 diabetes impair cardiac post-ischemic recovery through an arginase-dependent modulation of nitric oxide synthase and reactive oxygen species.
        JACC Basic Transl Sci. 2018; 3: 450-463
        • Xiong Y.
        • Yepuri G.
        • Forbiteh M.
        • Yu Y.
        • Montani J.P.
        • Yang Z.
        • Ming X.F.
        ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis.
        Autophagy. 2014; 10: 2223-2238
        • Ihling C.
        • Bohrmann B.
        • Schaefer H.E.
        • Technau-Ihling K.
        • Loeffler B.M.
        Endothelin-1 and endothelin converting enzyme-1 in human atherosclerosis--novel targets for pharmacotherapy in atherosclerosis.
        Curr. Vasc. Pharmacol. 2004; 2: 249-258
        • Weber C.
        • Zernecke A.
        • Libby P.
        The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models.
        Nat. Rev. Immunol. 2008; 8: 802-815
        • Gonon A.T.
        • Jung C.
        • Katz A.
        • Westerblad H.
        • Shemyakin A.
        • Sjoquist P.O.
        • Lundberg J.O.
        • Pernow J.
        Local arginase inhibition during early reperfusion mediates cardioprotection via increased nitric oxide production.
        PLoS One. 2012; 7e42038
        • Ryoo S.
        • Bhunia A.
        • Chang F.
        • Shoukas A.
        • Berkowitz D.E.
        • Romer L.H.
        OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signaling.
        Atherosclerosis. 2011; 214: 279-287
        • Pernow J.
        • Jung C.
        Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal?.
        Cardiovasc. Res. 2013; 98: 334-343
        • Rafnsson A.
        • Shemyakin A.
        • Pernow J.
        Selective endothelin ETA and dual ET(A)/ET(B) receptor blockade improve endothelium-dependent vasodilatation in patients with type 2 diabetes and coronary artery disease.
        Life Sci. 2014; 118: 435-439
        • Khallou-Laschet J.
        • Varthaman A.
        • Fornasa G.
        • Compain C.
        • Gaston A.T.
        • Clement M.
        • Dussiot M.
        • Levillain O.
        • Graff-Dubois S.
        • Nicoletti A.
        • Caligiuri G.
        Macrophage plasticity in experimental atherosclerosis.
        PLoS One. 2010; 5e8852
        • Griffiths H.R.
        • Gao D.
        • Pararasa C.
        Redox regulation in metabolic programming and inflammation.
        Redox Biol. 2017; 12: 50-57
        • Bohm F.
        • Ahlborg G.
        • Johansson B.L.
        • Hansson L.O.
        • Pernow J.
        Combined endothelin receptor blockade evokes enhanced vasodilatation in patients with atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 674-679
        • Bohm F.
        • Settergren M.
        • Gonon A.T.
        • Pernow J.
        The endothelin-1 receptor antagonist bosentan protects against ischaemia/reperfusion-induced endothelial dysfunction in humans.
        Clin. Sci. (Lond.). 2005; 108: 357-363

      Linked Article

      • Linking regulation of nitric oxide to endothelin-1: The Yin and Yang of vascular tone in the atherosclerotic plaque
        AtherosclerosisVol. 292
        • Preview
          A healthy endothelium prevents the development of atherosclerosis through protective effects on vasomotion, platelet adhesion, leukocyte trafficking, anti-inflammatory and anti-oxidant properties [1]. Nitric oxide and endothelin-1, autocrine and paracrine factors produced by endothelial cells, have opposing effects on smooth muscle cells contraction. The net balance between these pleiotropic molecules contributes to the regulation of local vascular tone. Nitric oxide (NO), the most potent vasodilatory molecule produced in the arterial wall, mediates endothelium-dependent relaxation (EDR).
        • Full-Text
        • PDF